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Re-expression of estrogen receptor alpha in estrogen receptor alpha-negative MCF-7 cells restores both estrogen and insulin-like growth factor-mediated signaling and growth.
Cancer Res. 2001 Aug 01; 61(15):5771-7.CR

Abstract

Estrogen can increase insulin-like growth factor-I receptor (IGF-IR) and insulin receptor substrate-1 (IRS-1) expression, two key components of IGF-I-mediated signaling. The result is sensitization of breast cancer cells to IGF-I and synergistic growth in the presence of estrogen and IGF-I. We hypothesized that loss of estrogen receptor alpha (ERalpha) would result in reduced IGF-mediated signaling and growth. To test this hypothesis, we examined IGF-I effects in MCF-7 breast cancer cell sublines that have been selected for loss of ERalpha (C4 and C4-12 cells are ERalpha-negative) by long-term estrogen withdrawal. C4 and C4-12 cells had reduced IGF-IR and IRS-1 mRNA and protein expression (compared with MCF-7 cells) that was not inducible by estrogen. Furthermore, C4 and C4-12 cells showed reduced IGF-I signaling and failed to show any growth response to either estrogen or IGF-I. To prove that loss of IGF and estrogen-mediated signaling and growth was a consequence of loss of ERalpha, we re-expressed ERalpha in C4-12 cells by stable transfection with HA-tagged ERalpha. Three independent C4-12 ERalpha-HA clones expressed a functional ERalpha that (a) was down-regulated by estrogen, (b) conferred estrogen-induction of cyclin D1 expression, and (c) caused estrogen-mediated increase in the number of cells in S phase. All of the effects were completely blocked by antiestrogens. Interestingly, ERalpha-HA expression in C4-12 cells did not restore estrogen induction of progesterone receptor expression. However, ERalpha-positive C4-12 cells now exhibited estrogen-induction of IGF-IR and IRS-1 levels and responded mitogenically to both estrogen and IGF-I. These data show that ERalpha is a critical requirement for IGF signaling, and to our knowledge this is the first report of functional ERalpha expression that confers estrogen-mediated growth of an ER-negative breast cancer cell line.

Authors+Show Affiliations

Breast Center, Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

11479214

Citation

Oesterreich, S, et al. "Re-expression of Estrogen Receptor Alpha in Estrogen Receptor Alpha-negative MCF-7 Cells Restores Both Estrogen and Insulin-like Growth Factor-mediated Signaling and Growth." Cancer Research, vol. 61, no. 15, 2001, pp. 5771-7.
Oesterreich S, Zhang P, Guler RL, et al. Re-expression of estrogen receptor alpha in estrogen receptor alpha-negative MCF-7 cells restores both estrogen and insulin-like growth factor-mediated signaling and growth. Cancer Res. 2001;61(15):5771-7.
Oesterreich, S., Zhang, P., Guler, R. L., Sun, X., Curran, E. M., Welshons, W. V., Osborne, C. K., & Lee, A. V. (2001). Re-expression of estrogen receptor alpha in estrogen receptor alpha-negative MCF-7 cells restores both estrogen and insulin-like growth factor-mediated signaling and growth. Cancer Research, 61(15), 5771-7.
Oesterreich S, et al. Re-expression of Estrogen Receptor Alpha in Estrogen Receptor Alpha-negative MCF-7 Cells Restores Both Estrogen and Insulin-like Growth Factor-mediated Signaling and Growth. Cancer Res. 2001 Aug 1;61(15):5771-7. PubMed PMID: 11479214.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Re-expression of estrogen receptor alpha in estrogen receptor alpha-negative MCF-7 cells restores both estrogen and insulin-like growth factor-mediated signaling and growth. AU - Oesterreich,S, AU - Zhang,P, AU - Guler,R L, AU - Sun,X, AU - Curran,E M, AU - Welshons,W V, AU - Osborne,C K, AU - Lee,A V, PY - 2001/8/2/pubmed PY - 2001/8/17/medline PY - 2001/8/2/entrez SP - 5771 EP - 7 JF - Cancer research JO - Cancer Res VL - 61 IS - 15 N2 - Estrogen can increase insulin-like growth factor-I receptor (IGF-IR) and insulin receptor substrate-1 (IRS-1) expression, two key components of IGF-I-mediated signaling. The result is sensitization of breast cancer cells to IGF-I and synergistic growth in the presence of estrogen and IGF-I. We hypothesized that loss of estrogen receptor alpha (ERalpha) would result in reduced IGF-mediated signaling and growth. To test this hypothesis, we examined IGF-I effects in MCF-7 breast cancer cell sublines that have been selected for loss of ERalpha (C4 and C4-12 cells are ERalpha-negative) by long-term estrogen withdrawal. C4 and C4-12 cells had reduced IGF-IR and IRS-1 mRNA and protein expression (compared with MCF-7 cells) that was not inducible by estrogen. Furthermore, C4 and C4-12 cells showed reduced IGF-I signaling and failed to show any growth response to either estrogen or IGF-I. To prove that loss of IGF and estrogen-mediated signaling and growth was a consequence of loss of ERalpha, we re-expressed ERalpha in C4-12 cells by stable transfection with HA-tagged ERalpha. Three independent C4-12 ERalpha-HA clones expressed a functional ERalpha that (a) was down-regulated by estrogen, (b) conferred estrogen-induction of cyclin D1 expression, and (c) caused estrogen-mediated increase in the number of cells in S phase. All of the effects were completely blocked by antiestrogens. Interestingly, ERalpha-HA expression in C4-12 cells did not restore estrogen induction of progesterone receptor expression. However, ERalpha-positive C4-12 cells now exhibited estrogen-induction of IGF-IR and IRS-1 levels and responded mitogenically to both estrogen and IGF-I. These data show that ERalpha is a critical requirement for IGF signaling, and to our knowledge this is the first report of functional ERalpha expression that confers estrogen-mediated growth of an ER-negative breast cancer cell line. SN - 0008-5472 UR - https://www.unboundmedicine.com/medline/citation/11479214/Re_expression_of_estrogen_receptor_alpha_in_estrogen_receptor_alpha_negative_MCF_7_cells_restores_both_estrogen_and_insulin_like_growth_factor_mediated_signaling_and_growth_ L2 - http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=11479214 DB - PRIME DP - Unbound Medicine ER -